The Blue Baby Syndromes

A New Syndrome?

In the 1980s a new phenomenon seemed to appear, namely, a form of infantile methemoglobinemia associated with inflammatory bowel disease (including diarrhea, acidosis, infection and gastroenteritis), where exposure to excessive nitrates could not be clearly established. The first of these reports appeared around 1982. Over the course of a year the authors had seen 11 infants with the triad of methemoglobinemia, diarrhea and acidosis. All were under three months of age, and all lived in homes with municipal water supplies. Although infection was suspected in at least some of these cases, no common fecal pathogens were isolated.

In the same year, a report from Israel described a study of 58 infants, age one week to one and a half years, admitted to the hospital for acute diarrhea. Over 100 admitted infants without gastrointestinal disturbances served as controls. All were fed the same milk, food and water, which had been analyzed for nitrates and nitrites. The study excluded infants with confounding factors such as genetic defects or exposure to drugs or chemicals that generate methemoglobin. None of the affected infants was said to be cyanotic, and only 12 of the 58 had methemoglobin levels above 8 percent. However, infants with the more severe diarrhea seemed to have higher methemoglobin levels. The nitrate concentration of the drinking water was well under the U.S. standard, and the diet was unusually low in nitrates. There was no clear correlation of the degree of acidosis and methemoglobin levels.

The most seminal observation was that the affected infants had high blood levels of nitrate, and those levels did appear to parallel the degree of methemoglobinemia. Affected infants excreted several times more nitrate in their urine than they consumed in their diet. In the control group the urinary excretion of nitrate was about the same as the daily intake or only slightly higher. Previously, scientists at the Massachusetts Institute of Technology had demonstrated nitrate production within the body in germ-free rats.

As is often the case, these two reports opened the floodgates. Between 1983 and 1996 reports of more than 90 cases came out in the medical literature, and then, maddeningly, the reports stopped appearing, just as they had with well-water methemoglobinemia 50 years before.

In 1999, Alex Avery of the Center for Global Food Issues at the Hudson Institute and his colleagues offered an ingenious explanation of the etiology after an analysis of some seemingly unrelated literature on inflammatory bowel disease. Noting that the earlier Israeli study strongly suggested that nitrites produced in the body were responsible for the methemoglobinemia and that their end product, nitrates, were elevated in urine and blood, they suggested the involvement of endogenous production of nitric oxide from arginine. The importance of nitric oxide as a normal biological mediator in a number of physiological processes has only recently been recognized. In solution, nitric oxide exists in equilibrium with nitrite. There is some published evidence to suggest that certain viral or bacterial infections of the bowel cause an increase in nitric oxide levels in human colonic epithelial cells. Although these studies were focused on explaining the pathologic changes in the bowel, they offer a possible explanation for the methemoglobinemia. That explanation, however, does not yet suggest why infants may be more susceptible.